Oxidative damage is present in the fatal brain edema of diabetic ketoacidosis

Hoffman, William H.; Siedlak, Sandra L.; Wang, Yang; Castellani, Rudy J.; Smith, Mark A.

doi:10.1016/j.brainres.2010.10.085

Cited by 40 publications

(42 citation statements)

References 73 publications

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“…Oxidative stress markers were elevated in the postmortem brains of two pediatric patients after fatal brain edema associated with DKA (23). Cerebrovascular dysfunction is caused by ROS directly and via tight junction modification and matrix metalloproteinase activation (39).…”

Section: Discussionmentioning

confidence: 98%

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Omatsu

Cepinskas

Clarson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under “flow” conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

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Section: Discussionmentioning

confidence: 98%

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Omatsu

Cepinskas

Clarson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…These disturbances in brain water balance can be viewed as being analogous to those associated with extrapontine myelinolysis, which is typically found in conjunction with fluid/electrolyte disturbances and has been associated with diabetes (21,22). The large U.K. case-control series of DKA-associated cerebral edema did not show an association with any changes in blood glucose after therapy (6).…”

Section: Discussionmentioning

confidence: 99%

Neurological Consequences of Diabetic Ketoacidosis at Initial Presentation of Type 1 Diabetes in a Prospective Cohort Study of Children

et al. 2014

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OBJECTIVETo investigate the impact of new-onset diabetic ketoacidosis (DKA) during childhood on brain morphology and function.RESEARCH DESIGN AND METHODSPatients aged 6–18 years with and without DKA at diagnosis were studied at four time points: <48 h, 5 days, 28 days, and 6 months postdiagnosis. Patients underwent magnetic resonance imaging (MRI) and spectroscopy with cognitive assessment at each time point. Relationships between clinical characteristics at presentation and MRI and neurologic outcomes were examined using multiple linear regression, repeated-measures, and ANCOVA analyses.RESULTSThirty-six DKA and 59 non-DKA patients were recruited between 2004 and 2009. With DKA, cerebral white matter showed the greatest alterations with increased total white matter volume and higher mean diffusivity in the frontal, temporal, and parietal white matter. Total white matter volume decreased over the first 6 months. For gray matter in DKA patients, total volume was lower at baseline and increased over 6 months. Lower levels of N-acetylaspartate were noted at baseline in the frontal gray matter and basal ganglia. Mental state scores were lower at baseline and at 5 days. Of note, although changes in total and regional brain volumes over the first 5 days resolved, they were associated with poorer delayed memory recall and poorer sustained and divided attention at 6 months. Age at time of presentation and pH level were predictors of neuroimaging and functional outcomes.CONCLUSIONSDKA at type 1 diabetes diagnosis results in morphologic and functional brain changes. These changes are associated with adverse neurocognitive outcomes in the medium term.

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“…Previous studies have demonstrated that the ketones, especially AA, can generate superoxide radicals and induce cytokine and adhesion molecule expression, and that ketonemic diabetics have high levels of oxidative stress compared to those of normoketonemic diabetic patients [13,14,16,20,24,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. We observed that AA was significantly able to upregulate NOX4 expression and NADPH oxidase activity, while BHB failed to produce any adverse effects in HUVEC.…”

Section: Discussionmentioning

confidence: 99%

Hyperketonemia (Acetoacetate) Upregulates NADPH Oxidase 4 and Elevates Oxidative Stress, ICAM-1, and Monocyte Adhesivity in Endothelial Cells

Marie

Jain

2015

Cell Physiol Biochem

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Background/Aims: The incidence of developing microvascular dysfunction is significantly higher in type 1 diabetic (T1D) patients. Hyperketonemia (acetoacetate, β-hydroxybutyrate) is frequently found along with hyperglycemia in T1D. Whether hyperketonemia per se contributes to the excess oxidative stress and cellular injury observed in T1D is not known. Methods: HUVEC were treated with ketones in the presence or absence of high glucose for 24 h. NOX4 siRNA was used to specifically knockdown NOX4 expression in HUVEC. Results: Ketones alone or in combination with high glucose treatment cause a significant increase in oxidative stress, ICAM-1, and monocyte adhesivity to HUVEC. Using an antisense approach, we show that ketone induced increases in ROS, ICAM-1 expression, and monocyte adhesion in endothelial cells were prevented in NOX4 knockdown cells. Conclusion: This study reports that elevated levels of ketones upregulate NOX, contributing to increased oxidative stress, ICAM-1 levels, and cellular dysfunction. This provides a novel biochemical mechanism that elucidates the role of hyperketonemia in the excess cellular injury in T1D. New drugs targeting inhibition of NOX seems promising in preventing higher risk of complications associated with T1D.

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Oxidative damage is present in the fatal brain edema of diabetic ketoacidosis

Cited by 40 publications

References 73 publications

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Neurological Consequences of Diabetic Ketoacidosis at Initial Presentation of Type 1 Diabetes in a Prospective Cohort Study of Children

Hyperketonemia (Acetoacetate) Upregulates NADPH Oxidase 4 and Elevates Oxidative Stress, ICAM-1, and Monocyte Adhesivity in Endothelial Cells

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